Trial Information

PRIMARY OBJECTIVES: I. To determine the progression-free survival of erlotinib (erlotinib)
and bevacizumab versus that of erlotinib alone for the purpose of deciding if the
combination arm is worth pursuing in a phase III trial. SECONDARY OBJECTIVES: I. To
investigate the overall survival of erlotinib and bevacizumab versus erlotinib alone. II. To
investigate the response rate of erlotinib and bevacizumab versus erlotinib alone. III. To
investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R
EGFR point mutations. IV. To investigate the toxicity of erlotinib and bevacizumab versus
erlotinib alone using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
TERTIARY OBJECTIVES: I. To correlate EGFR mutations detected in plasma deoxyribonucleic
acid (DNA) with those detected in tumor DNA. II. To estimate the prevalence of EGFR T790M
resistance mutations from pretreatment tumor biopsies using more sensitive mutation
detection methods. III. To investigate progression free survival of EGFR mutant NSCLC
patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen
using allele specific quantitative polymerase chain reaction (PCR). IV. To prospectively
evaluate the predictive value of plasma vascular endothelial growth factor A (VEGF-A) levels
on progression free survival in patients treated with erlotinib alone or in combination with
bevacizumab. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients
receive erlotinib orally (PO) once daily (QD) on days 1-21. ARM B: Patients receive
erlotinib as in Arm A and bevacizumab intravenously (IV) over 30-90 minutes on day 1. In
both arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity. After completion of study treatment, patients are followed up
periodically for up to 5 years.

Inclusion Criteria:

- Histologic documentation of primary lung carcinoma, non-squamous histology with
activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R
mutation) *Note: EGFR mutation testing must be performed at a Clinical Laboratory
Improvement Amendments (CLIA) certified lab; either institutional or through a
commercial laboratory (e.g. Genzyme, Response Genetics, etc); the laboratory report
from the commercial laboratories report the specific mutations detected, and the
method of detecting the exon 19 and exon 21 L858R point mutations must be available

- Stage IV disease according to the 7th Edition of the American Joint Committee on
Cancer staging system -Measureable disease- Life expectancy of >= 12 months

- Prior chemotherapy or treatment for metastatic non-small cell lung cancer Any of
the following because this study involves an investigational agent whose genotoxic,
mutagenic and teratogenic effects on the developing fetus and newborn are unknown *
Pregnant women * Nursing women * Men or women of childbearing potential who are
unwilling to employ adequate contraception Co-morbid systemic illnesses or other
severe concurrent disease which, in the judgment of the investigator, would make the
patient inappropriate for entry into this study or interfere significantly with the
proper assessment of safety and toxicity of the prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be human immunodeficiency virus (HIV) positive, per MD
discretion

- Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm

- Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: Non melanotic
skin cancer or carcinoma-in-situ of the cervix * Note: If there is a history of prior
malignancy, they must not be receiving other specific treatment (i.e. hormonal
therapy) for their cancer

- History of myocardial infarction or other evidence of arterial thrombotic disease
(angina) * Note: Allowed only if patient has no evidence of active disease for at
least 6 months prior to randomization

- Current or recent (=< 10 days prior to randomization use of aspirin (> 325 mg/day),
clopidogrel (> 75 mg/day), or current or recent (=< 10 days prior to randomization
use of full- dose (i.e. therapeutic dose) oral or parenteral anticoagulants or
thrombolytic agent for therapeutic purposes * Note: Prophylactic use of
anticoagulants is allowed

- Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical
procedure, open biopsy, or significant traumatic injury =< 28 days or core biopsy =<
7 days prior to randomization

- Known central nervous system (CNS) disease, except for treated brain metastasis *
Note: Treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, for at least
7 days as ascertained by clinical examination and brain imaging (magnetic resonance
imaging [MRI] or computed tomography [CT]) during the screening period;
anticonvulsants (stable dose) are allowed; treatment for brain metastases may include
whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator
[LINAC], or equivalent) or a combination as deemed appropriate by the treating
physician; patients with CNS metastases treated by neurosurgical resection or brain
biopsy performed =< 3 months prior to randomization will be excluded

Outcome Measure:

Outcome Description:

Described graphically using the Kaplan and Meier product limit estimator. Comparisons of PFS between arms will be conducted using a stratified log rank test. Cox proportional hazards model will be used to estimate the adjusted hazard ratios and their 95% confidence intervals. Hazard ratio for treatment effect will be estimated for each subgroup of patients that has significant interaction with treatment. The robustness of treatment effects in different patient subgroups will examined in Forest plots.

Outcome Time Frame:

From the date of randomization to the date of disease progression or death of any cause, assessed up to 5 years

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